Vaccinia virus is used to vaccinate persons to prevent disease with smallpox. Compared with other live virus vaccines, the smallpox vaccine is associated with frequent side effects including fever, a sore or swollen arm, headache, and fatigue. Other more serious side effects have also been reported including development of multiple lesions outside the vaccination site (generalized vaccinia), inflammation of the brain (postvaccinia encephalitis), severe infection of the skin in persons with a history of eczema (eczema vaccinatum), and disseminated vaccinia virus infection in immunocompromised persons (progressive vaccinia). Previously, we tested blood from 27 smallpox vaccine recipients and found that 4 of 202 blood samples (from 3 of 27 vaccine recipients) were positive for the smallpox vaccine virus in the blood by PCR, but none were positive by culture. The lack of finding infectious smallpox vaccine virus in the blood indicates that the current guidelines for deferral of blood donation from smallpox vaccine recipients are appropriate. We tested throat swabs from 28 smallpox vaccine recipients and found that 0 of 213 throat swabs were positive by culture and 0 of 190 throat swabs were positive by PCR. This study suggests that few, if any, healthy smallpox vaccine recipients shed the virus from their throat. Cytokines are proteins that are produced by white blood cells and secreted into the bloodstream that are important for trafficking of white blood cells to trigger inflammation. We hypothesize that induction of cytokines is associated with some of the side effects of smallpox vaccination. We are currently analyzing cytokines in the blood of subjects who received the smallpox vaccine and comparing responses in subjects vaccinated for the first time with those being vacccinated who had the received the vaccine previously. Identification of specific cytokines induced after vaccination may help to explain the pathogenesis of certain side effects associated with smallpox vaccination and might suggest new ways to modify some of these side effects.